The long-term objective of our research program has been, and continues to be, the elucidation of the basic mechanisms underlying accumulation of excess fluid in the extravascular spaces. In our current proposal, we focus on the basic microvascular, interstitial and lymphatic processes involved in causation of the edema of inflammation. The specific aims of our proposed research are: 1) to delineate the roles of pressure-dependent (i.e. mocrovascular smooth muscle-dependent) and permeability-dependent (i.e. endothelium-dependent) mechanisms in extravasation of fluid and proteins during exposure to inflammatory stimuli, 2) utilizing cell-free perfusates, to define the action of chemical mediators of inflammation on microvascular permeability to macromolecules in the absence of formed blood elements, 3) to establish the ultrastructural and functional linkages between neutrophil/endothelium interactions and macromolecular extravasation, 4) to quantify the contribution of specific neutrophil-derived permeability-altering mediators to the macromolecular extravasation elicited by in vivo and in vitro activation of the leukocytes, 5) utilizing umbilical tissue and corneal stroma as model matrices, to elucidate the role of neutrophil-derived substances on the compliance, exclusion and transport properties of the interstitium, and 6) to determine the impact of inflammatory mediators on the function contractile lymph vessels. The proposed research should yield new insights into the causes and treatment of inflammatory reactions in the microvasculature, interstitium and lymphatics.